Esters of p-carbonylphenoxy-isobutyric acids

ABSTRACT

This invention is concerned with esters of p-carbonylphenoxy-isobutyric acids of the general formulae: ##STR1## wherein R is a phenyl group substituted by one or two halogen atoms; 
     R&#39; is H, CH 3 , C 6  H 5 , SCH 3 , OCH 3 , or, SO 2  CH 3  ; 
     R&#34; is CH 3  or C 2  H 5  ; 
     Y is C 1  -C 4  alkoxy, phenoxy, phenoxy substituted by one or two halogen atoms, or, OCH 2  O--CO--C(CH 3 ) 3  ; 
     Z is C 1  -C 4  alkyl, phenyl or R; 
     NR 1  R 2  is N(CH 3 ) 2  N(C 2  H 5 ) 2 , morpholino, piperidino, hexamethylenimino, pyrrolidino. 
     This invention is also concerned with acid addition salts obtained from formula Ia compounds with acids. 
     Compounds of formulae I and Ia are useful as hypocholesterolemiant and hypolipidemiant agents.

This application is a divisional application of application Ser. No.600,127 filed on July 29, 1975 now U.S. Pat. No. 4,058,552 which was acip application of my previous U.S. patent application Ser. No. 326,188of Jan. 24, 1973 now U.S. Pat. 3,907,792 which was itself a cipapplication of my U.S. patent application Ser. No. 8071 of Feb. 2, 1970now U.S. Pat. No. 3,914,286.

This invention is concerned with esters of p-carbonylphenoxy-isobutyricacids.

This application is concerned with esters of the general formulae##STR2## wherein R is a phenyl group substituted by one or two halogenatoms;

R' is H, CH₃, C₆ H₅, SCH₃, OCH₃, or, SO₂ CH₃ ;

R" is CH₃ or C₂ H₅

Y is C₁ -C₄ alkoxy, phenoxy, phenoxy substituted by one or two halogenatoms, or OCH₂ O--CO--C(CH₃)₃ ;

Z is C₁ -C₄ alkyl, phenyl, or, R

NR₁ R₂ is N(CH₃)₂ N(C₂ H₅)₂, morpholino, piperidino, pyrrolidino, or,hexamethylenimino.

This application is also concerned with acid addition salts obtainedfrom formula Ia compounds with inorganic and organic acids.

All the compounds of formula I and Ia have useful therapeuticproperties. All of them are lipids and cholesterol reducing agents,moreover they act as normolipidemiant and hypocholesterolemiant agents.The acids (Y=OH): from which esters I and Ia are derived, induce gastriculcers when administered by oral route, while their ester derivatives Iand Ia do not develop gastric ulcers.

Some acids of the isobutyric type have been previously disclosed orsuggested. AINSWORTH et al, J. Med. Chem., (1967), 10, 158-161 describedtwo acids, namely the p-hexanoyl- and p-octanoylphenoxyisobutyric acids.NAKANISHI (U.S. Pat. No. 3,494,957) suggested thep-acetylphenoxy-isobutyric acid. CRAGOE (U.S. Pat. No. 3,704,314)suggested two acids, namely the p-butyrylphenoxy isobutyric acid and2,3-dichloro-4-(2-methylenebutyryl-phenoxy-isobutyric acid, and anester, namely the ethyl p-formylphenoxy-isobutyrate. On one hand theseknown acids present the disadvantage of inducing gastric ulcers, and onthe other hand ethyl p-formylphenoxy-isobutyrate is less active thanClofibrate taken as a reference product. By halogen atoms I meanfluorine, chlorine, bromine and iodine atoms, the preferred halogen atombeing chlorine. Thus, in the definition of R are included within thescope of this invention the 4-chlorophenyl, 3-chlorophenyl,3,4-dichlorophenyl and 2,6-dichlorophenyl groups. The preferred R groupis 4-chlorophenyl. The preferred R' and R" are respectively R'=H andR"=CH₃.

The esters of formula I are more active than their homologue compoundsin which R is alkyl or cycloalkyl such as cyclohexyl. Moreover when theesters are p-carbonylphenoxy-isobutyric acid aminoethyl esters (i.e.compounds of the formula Ia), it is noticed that the presence of theOCH₂ CH₂ NR₁ R₂ group enhances the hypocholesterolemiant andhypolipidemiant activities of the p-alkylcarbonyl compounds.

The preferred compound, that is to say the most useful therapeutically,is the isopropyl p-(4-chlorobenzoyl)-phenoxy-isobutyrate of formula I,which is coded as No. 178. Then comes the fumarate of β-azepino-ethylp-(4-chlorobenzoyl)-phenoxy-isobutyrate of formula Ia, which is coded asNo. 229.

The isobutyric acids (Y=OH) can be synthesized according to a methodknown per se. The methods I recommend are summed up by the followingreaction schemes A and B, scheme B being the preferred one since itgives higher yields than A. ##STR3##

The esters I and Ia are obtained from the acids by a known process. Forinstance the esters may be prepared by esterification from thecorresponding acids or by transesterification from another ester. Forobtaining esters Ia the transesterification method is preferred.

Preparation I

p-(4-Chlorobenzoyl)-phenoxy-isobutyric acid

(Code No. 153)

1 mole of 4-hydroxy-4'-chlorobenzophenone is dissolved in anhydrousacetone and then 5 moles of powdered sodium hydroxide is added. Thecorresponding sodium phevate precipitates. Refluxing is effected, andthen, 1:5 mole of CHCl₃ diluted with anhydrous acetone is added and theresulting mixture is refluxed for 10 hours. After cooling, water isadded, the acetone is evaporated, the aqueous phase is washed with etherand acidified and the organic phase is redissolved in ether andextracted into a solution of bicarbonate. The bicarbonate solution isthen acidified to obtain the desired acid, having a melting point of185° C., with a yield of 75%.

Preparation II ##STR4##

1 mole of the acid obtained in preparation I is converted into its acidchloride using thionyl chloride (2:5 moles). 1 mole of the acid chlorideis then condensed with 1:05 mole of isopropyl alcohol in the presence of0:98 mole of pyridine in an inert solvent such as benzene.

Since traces of SO₂ (which has a bad smell) may be obtained from thethionyl chloride; it is preferable to avoid this disadvantage bycarrying out the esterification directly.

In table I, I have given examples of p-carbonylphenoxy-isobutyric acidswhich are used as intermediate compounds for the preparation of theesters according to this invention. They have been obtained according toreaction scheme A or B.

Tables II and III are respectively concerned with esters of formula Iand esters of formula Ia. I have given in Table IV reference orcomparison products. Moreover, p-alkylcarbonyl-phenoxy-isobutyric acidesters of table IV may be used for preparing the corresponding esters Iaby transesterification.

                  TABLE I                                                         ______________________________________                                         ##STR5##                                                                     Ex-   Code                            Melting or                              ample No.    R           R'      R"   Boiling point                           ______________________________________                                        Ex 1  82     CH.sub.3 CH.sub.2                                                                         H       CH.sub.3                                                                           F = 96° C.                       Ex 2.sup.(a) C.sub.6 H.sub.5                                                                           H       CH.sub.3                                     Ex 3.sup.(b) CH.sub.3 (CH.sub.2).sub.4                                                                 H       CH.sub.3                                     Ex 4.sup.(b) CH.sub.3 (CH.sub.2).sub.6                                                                 H       CH.sub.3                                     Ex 5.sup.(c) CH.sub.3    H       CH.sub.3                                     Ex 6.sup.(a)                                                                    .sup.(d)   CH.sub.3 (CH.sub.2).sub.2                                                                 H       CH.sub.3                                                                           F = 88° C.                       Ex 7  153    4-ClC.sub.6 H.sub.4                                                                       H       CH.sub.3                                                                           F = 185° C.                      Ex 8  198    CH.sub.3 (CH.sub.2).sub.3                                                                 H       CH.sub.3                                                                           F = 62° C.                       Ex 9  243    CH.sub.3    3-CH.sub.3                                                                            CH.sub.3                                                                           F = 98° C.                       Ex 10 --     CH.sub. 3   2-C.sub.6 H.sub.5                                                                     CH.sub.3                                                                           F = 106° C.                      Ex 11 305    4-ClC.sub.6 H.sub.4                                                                       H       C.sub.2 H.sub.5                                                                    F = 140° C.                      Ex 12 406    3-ClC.sub.6 H.sub.4                                                                       H       CH.sub.3                                                                           F = 121° C.                      Ex 13 404    3,4-Cl.sub.2C.sub.6 H.sub.3                                                               H       CH.sub.3                                                                           F = 155° C.                      Ex 14 401    2,6-Cl.sub.2C.sub.6 H.sub.3                                                               H       CH.sub.3                                                                           F = 196° C.                      Ex 15 391    cyclohexyl  H       CH.sub.3                                                                           F = 146° C.                      Ex 16 --     CH.sub.3    3-SO.sub.2 CH.sub.3                                                                   CH.sub.3                                                                           --                                      ______________________________________                                         Notes                                                                         .sup.(a) disclosed in my previous U.S. Pat. application SN 8071               .sup.(b) disclosed by AINSWORTH                                               .sup.(c) suggested by NAKANISHI                                               .sup.(d) suggested by CRAGOE                                             

                                      TABLE II                                    __________________________________________________________________________     ##STR6##                                                                                                      Melting or                                        Code                        Boiling                                      Example                                                                            No.                                                                              R        R'   Y          point                                        __________________________________________________________________________    Ex 17                                                                              162                                                                              4-ClC.sub.6 H.sub.4                                                                    H    OCH.sub.3  F = 89° C.                            Ex 18                                                                              163                                                                              4-ClC.sub.6 H.sub.4                                                                    H    OC.sub.2 H.sub.5                                                                         F = 79° C.                            Ex 19                                                                              178                                                                              4-ClC.sub.6 H.sub.4                                                                    H    OCH(CH.sub.3).sub.2                                                                      F = 78° C.                            Ex 20                                                                              217                                                                              4-ClC.sub.6 H.sub.4                                                                    H    p-OCH.sub.6 H.sub.4 Cl                                                                   F = 135° C.                           Ex 21                                                                              403                                                                              3-ClC.sub.6 H.sub.4                                                                    H    OCH(CH.sub.3).sub.2                                                                      F = 79° C.                            Ex 22                                                                              405                                                                              3,4-Cl.sub.2C.sub.6 H.sub.3                                                            H    OCH(CH.sub.3).sub.2                                                                      F = 69° C.                            Ex 23                                                                              402                                                                              2,6-Cl.sub.2C.sub.6 H.sub.3                                                            H    OCH(CH.sub.3).sub.2                                                                      F = 115° C.                           Ex 24                                                                              253                                                                              4-ClC.sub.6 H.sub.4                                                                    3-CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                       --                                          Ex 25                                                                              297                                                                              4-ClC.sub.6 H.sub.4                                                                    H    OCH.sub.2 OCOC(CH.sub.3).sub.3                                                           F = 80° C.                            __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________     ##STR7##                                                                                                  Melting or                                            Code                    Boiling                                          Example                                                                            No.                                                                              Z      R'                                                                              OCH.sub.2 CH.sub.2 NR.sub.1 R.sub.2                                                       point                                            __________________________________________________________________________    Ex 26                                                                              208                                                                              C.sub.6 H.sub.5                                                                      H                                                                                ##STR8##   F = 100° C.                               Ex 27                                                                              209                                                                              C.sub.6 H.sub.5                                                                      H                                                                                ##STR9##   F = 118° C.                               Ex 28                                                                              210                                                                              CH.sub.3                                                                             H                                                                                ##STR10##  F = 134° C.                               Ex 29                                                                              211                                                                              C.sub.6 H.sub.5                                                                      H                                                                                ##STR11##  F = 115° C.                               Ex 30                                                                              212                                                                              C.sub.6 H.sub.5                                                                      H OCH.sub.2 CH.sub.2 Net.sub.2                                                              F = 62° C.                                                 maleate                                                      Ex 31                                                                              229                                                                              4-ClC.sub.6 H.sub.4                                                                  H                                                                                ##STR12##  F = 120° C.                               Ex 32                                                                              230                                                                              4-ClC.sub.6 H.sub.4                                                                  H OCH.sub.2 CH.sub.2 Net.sub.2                                                              F = 104° C.                                                HCl                                                          Ex 33                                                                              231                                                                              4-ClC.sub.6 H.sub.4                                                                  H                                                                                ##STR13##  F = 116° C.                               Ex 34                                                                              232                                                                              CH.sub.3 (CH.sub.2).sub.3                                                            H OCH.sub.2 CH.sub.2 Net.sub.2                                                              F = 72° C.                                                 HCl                                                          Ex 35                                                                              233                                                                              CH.sub.3 (CH.sub.2).sub.3                                                            H                                                                                ##STR14##  F = 118° C.                               Ex 36                                                                              239                                                                              4-ClC.sub.6 H.sub.5                                                                  H                                                                                ##STR15##  F = 145° C.                               __________________________________________________________________________

                                      TABLE IV                                    __________________________________________________________________________    Reference, comparison and/or other intermediate compounds                      ##STR16##                                                                                                   Melting or                                          Code                      Boiling                                        Example                                                                            No.                                                                              R      R'    Y         point                                          __________________________________________________________________________    Ex 37.sup.(c)                                                                      180                                                                              C.sub.6 H.sub.5                                                                      H     OCH.sub.3 F = 58° C.                              Ex 38.sup.(a)                                                                      186                                                                              C.sub.6 H.sub.5                                                                      H     OC.sub.2 H.sub.5                                                                        F = 87° C.                              Ex 39.sup.(a)                                                                      190                                                                              C.sub.6 H.sub.5                                                                      H     OCH(CH.sub.3).sub.2                                                                     F = 84° C.                              Ex 40                                                                              -- CH.sub.3                                                                             H     OC.sub.2 H.sub.5                                                                        E.sub.0.03 = 120° C.                    Ex 41                                                                              -- CH.sub.3 CH.sub.2 CH.sub.2                                                           H     OC.sub.2 H.sub.5                                                                        E.sub.0.005 = 144°                      Ex 42                                                                              140                                                                              CH.sub.3                                                                             H     OCH.sub.3 F = 62° C.                              Ex 43                                                                              188                                                                              CH.sub.3 (CH.sub.2).sub.3                                                            H     OCH.sub.3 E.sub.0.05 = 147-9°                     Ex 44                                                                              187                                                                              CH.sub.3 (CH.sub.2).sub.3                                                            H     OC.sub.2 H.sub.5                                                                        E.sub.0.05 = 157-8°                     Ex 45                                                                              189                                                                              CH.sub.3 (CH.sub.2).sub.3                                                            H     OCH(CH.sub.3).sub.2                                                                     E.sub.0.05 = 156-7°                     Ex 46                                                                              -- H      H     OC.sub.2 H.sub.5                                                                        --                                             Ex 47                                                                              390                                                                              cyclohexyl                                                                           H     OCH(CH.sub.3).sub.2                                                                     F = 148° C.                             Ex 48                                                                              238                                                                              4-ClC.sub.6 H.sub.5                                                                  H                                                                                    ##STR17##                                                                              F = 144° C.                             Ex 49                                                                              240                                                                              CH.sub.3                                                                             3-CH.sub.3                                                                          OCH.sub.3 E.sub.0.05 = 132° C.                    Ex 50                                                                              241                                                                              CH.sub.3                                                                             3-CH.sub.3                                                                          OC.sub.2 H.sub.5                                                                        E.sub.0.05 = 136° C.                    Ex 51                                                                              242                                                                              CH.sub.3                                                                             3-CH.sub.3                                                                          OCH(CH.sub.3).sub.2                                                                     E.sub.0.05 = 139° C.                    Ex 52                                                                              -- CH.sub.3                                                                             3-SCH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                     E.sub.1 = 198° C.                       Ex 53                                                                              -- CH.sub.3                                                                             3-SO.sub.2 CH.sub.3                                                                 OCH(CH.sub.3).sub.2                                                                     F = 86° C.                              Ex 54                                                                              -- CH.sub. 3                                                                            2-C.sub.6 H.sub.5                                                                   OCH(CH.sub.3).sub.2                                                                     F = 95° C.                              __________________________________________________________________________     Notes                                                                         .sup.(a) and .sup.(c) see table I                                        

The hypolipemiant and hypocholesterolemiant properties were exhibited inthe rat. Each batch of rats (15 animals) is put on a fast at time t=0. Ablood sample is taken at time t+15 hours, and then each product beingtested is immediately administered orally. A new blood sample is takenat time t+39 hours. The variation (diminution) in the total amount ofblood cholesterol and total amount of blood lipids is measured betweent+15 hours and t+39 hours, and this variation is expressed in % in TableV in which the results obtained with the products according to thisinvention and reference products are shown.

The invention also relates to therapeutic compositions containing, incombination with a physiologically acceptable excipient, at least onecompound of formula I or Ia or one of their non-toxic acid-additionsalts.

                  TABLE V                                                         ______________________________________                                                              variation   variation                                   Example     dosage    cholesterol lipids                                      (Code No.)  mg/kg     %           %                                           ______________________________________                                        Ex 19 (178)  50       -30         -32                                         Ex 21 (403) 100       -21         -18                                         Ex 22 (405) 100       -10         - 4                                         Ex 23 (402) 100       - 9         - 5                                         Ex 27 (209)  75       -19         -34                                         Ex 31 (229)  50       -35         -34                                         Ex 36 (239)  50       -18         -22                                         Ex 24 (253)  70       -15         -25                                         Ex 28 (210) 400       -35         -16                                         Ex 35 (233) 300       -16         -15                                         Ex 38 (186) 100       -21         -32                                         Ex 39 (190)  50       -30         -32                                         Ex 40       300       -28         -34                                         Ex 41       400       -22         -31                                         Ex 47 (390) 100       N.S.        - 3                                         ______________________________________                                    

What is claimed is:
 1. A novel ester of p-carbonylphenoxy-isobutyric acid selected from the group consisting of(a) compounds of the formula ##STR18## wherein R' is H, CH₃, C₆ H₅, SCH₃, OCH₃, or SO₂ CH₃ ;R" is CH₃ or C₂ H₅ ; Z is a phenyl group substituted by one halogen atom and NR₁ R₂ is N(CH₃)₂, N(C₂ H₅)₂, morpholino, piperidino, hexamethylenimino or pyrrolidino, and (b) non-toxic acid addition salt thereof.
 2. A novel ester of p-carbonylphenoxy-isobutyric acid having the formula ##STR19## wherein Z is a 4-chlorophenyl group, and NR₁ R₂ is N(C₂ H₅)₂, morpholino, piperidino or hexamethylenimino; and its non-toxic acid addition salts.
 3. A novel ester of p-carbonylphenoxy-isobutyric-acid having the formula ##STR20## wherein Z is C₁ -C₄ alkyl, phenyl or chlorophenyl and NR₁ R₂ is a hexamethylenimino group and non-toxic acid addition salts thereof.
 4. A novel ester according to claim 1 in which NR₁ R₂ is a hexamethylenimino group.
 5. β-hexamethyleniminoethyl-p-(4-chlorobenzoyl)-phenoxy-isobutyrate and its non-toxic acid addition salts.
 6. A novel ester of the formula ##STR21## and nontoxic acid addition salts thereof.
 7. A novel ester of the formula ##STR22## and nontoxic acid addition salts thereof.
 8. A novel ester of the formula ##STR23## and nontoxic acid addition salts thereof.
 9. A novel ester of the formula ##STR24## and nontoxic acid addition salts thereof.
 10. A therapeutic composition useful for treating patients in order to reduce their blood cholesterol and lipids content, which comprises, in association with a pharmaceutically acceptable excipient, a therapeutically effective amount of at least a compound according to any one of claims 1, 2, 3 or 6-11.
 11. A novel ester of the formula ##STR25## and nontoxic acid addition salts thereof. 